The human immunodeficiency virus (“HIV”) is the causal agent for acquired immunodeficiency syndrome (“AIDS”), and its precursor AIDS-related complex (“ARC”). AIDS is a: disease characterized by the destruction of the immune system, particularly the destruction of CD4+ T-cells, with attendant susceptibility to opportunistic infections. ARC is a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever, and weight loss.
Among the drugs currently used to treat HIV infections in humans are those that inhibit the HIV aspartyl protease enzyme. Drugs that are used as protease inhibitors are, in general, chemically complex and are difficult to prepare in a cost-effective and efficient manner.
For example, WO 94/26749 discloses the preparation of the intermediate hexahydrofuro[2,3-b]furan-3-ol, as well as its use in the preparation of compounds that are effective inhibitors of HIV aspartyl protease. This method disclosed for the preparation of the hexahydrofuro[2,3-b]furan-3-ol subunit is a multi-step procedure that relies on a citrate derivative as starting material. This method requires the initial preparation of an enantiomerically pure starting material, followed by six additional chemical steps. A more efficient method would be preferable for savings in time, materials, and other valuable resources.
Another synthesis of the intermediate hexahydrofuro[2,3-b]furan-3-ol subunit was described by Ghosh, et. al. in Nonpeptidal P2 Ligands for HIV Protease Inhibitors: Structure-Based Design, Synthesis and Biological Evaluation, J. Med. Chem., 39(17), p.3278, 1996. A key step in this preparation of the hexahydrofuro[2,3-b]furan ring system is the cyclization of a 2-(2-propynyloxy)tetrahydrofuranyl derivative under radical cyclization conditions. For example, 3-iodo-2-(2-propynyloxy)tetrahydrofuran could be cyclized to the desired 3-methylene hexahydrofuro[2,3-b]furan derivative using stoichiometric amounts of compounds capable of acting as radical initiators, such as a mixture of sodium borohydride and cobaloxime. Alternatively, the same cyclization reaction can be effected using a stoichiometric amount of a trialkyltin hydride, such as tributyltin hydride. There are disadvantages, however, to such methods for the synthesis of pharmaceutical intermediates. For example, the toxicity of trace amounts of metals such as cobalt or tin poses a potential disadvantage of such methods.
Based upon the disadvantages of the present methods for the formation of protease inhibitor intermediates, new and more efficient methods for their preparation are of value. Preferably, any new method would use readily available, achiral starting materials. Additionally, the method preferably consists of fewer chemical steps than previously published methods and, therefore, be more amenable to scale-up synthesis.